eMedicine Specialties > Pediatrics: General Medicine > Hematology

Polycythemia Vera: Differential Diagnoses & Workup

Author: Josef T Prchal, MD, FRCP, Professor of Medicine (Hematology), Adjunct Professor of Pathology and Genetics, University of Utah School of Medicine
Coauthor(s): Scott J Samuelson, MD, Fellow in Hematology and Oncology, Huntsman Cancer Institute, University of Utah School of Medicine
Contributor Information and Disclosures

Updated: Sep 3, 2009

Differential Diagnoses

Other Problems to Be Considered

• Polycythemia vera (PV) must be differentiated from other causes of polycythemia. The polycythemias can be subdivided by etiology into 3 groups: apparent or relative polycythemia, primary polycythemia, and secondary polycythemia.
• A quick way to screen for polycythemia vera without excessive diagnostic testing is to determine if a hereditary pattern to the erythrocytosis is present. Because polycythemia vera is an acquired disorder, a familial pattern weighs against such a diagnosis; familial polycythemia vera has been reported, but in contrast with other familial polycythemias, the family clustering of polycythemia vera is associated with absence of phenotype at birth and an acquired polycythemic phenotype later in life. Rather, the phenotype at birth suggests the diagnoses such as high-affinity hemoglobin mutations, low 2,3 bisphosphoglycerate levels (BPG), primary familial and congenital polycythemia (PFCP), Chuvash polycythemia or rare mutations of HIF2a, or proline dehydrogenase type 2 genes. These disorders should be referred to a hematologist who is an expert in this area for specialized diagnostic testing and management.
• Apparent or relative polycythemia is due to a decrease in plasma volume with a normal red cell mass. It is associated with hypertension, obesity, dehydration and stress, among other causes. 
• Primary polycythemia is caused by intrinsic hyperproliferation of the hematopoietic stem cell independent of erythropoietin (Epo) stimulation or with exaggerated response to a low Epo level. Polycythemia vera, in which the hematopoietic stem cell proliferates independently of erythropoietin, is the most common primary polycythemia. The defining features of polycythemia vera are described in the Introduction. Another primary polycythemia is PFCP. The defect in PFCP is hyper-responsiveness to erythropoietin. One of its genetic causes has been defined: a hyperfunctional Epo receptor (a gain-of-function mutation) involving deletion of the negative regulatory subunit of the erythropoietin receptor (EpoR). Other mutations independent of the EpoR mutation are present but are as yet undefined.
• Unlike polycythemia vera, which is a clonal acquired genetic mutation that can progress to leukemia, PFCP is a nonclonal germ line mutation that does not progress to acute leukemia. PFCP also differs from polycythemia vera in that only the erythroid lineage is affected.
• Secondary polycythemia is due to elevated levels of Epo that induce erythrocyte proliferation; however, at the time of presentation, the increased RBC mass might have reached an equilibrium, and the Epo level is often within normal limits. The normal Epo level, however, would be inappropriately high for the elevated hematocrit.  High Epo results from physiologically appropriate or inappropriate causes. 
• Physiologically appropriate secondary polycythemias result from hypoxia. Hypoxia is the common endpoint of the various causes of physiologically appropriate secondary polycythemias. 
• High-altitude polycythemia occurs because of lower ambient pO2 resulting in tissue hypoxia. Acute compensation occurs through hyperventilation, but chronic compensation involves elevation of hematocrit (although the degree of response varies between individuals). Not all populations accommodate to high altitude by polycythemia. The Tibetans have a lower hemoglobin level than expected but have high levels of exhaled nitric oxide, which may be the end product of a process improving oxygen delivery by inducing vasodilation and increasing blood flow to the tissues.
• In cardiopulmonary disease, impaired respiration and circulation result in tissue hypoxia and subsequently increased erythropoietin.
• Smoking results in the formation of carboxyhemoglobin that does not carry oxygen and results in higher oxygen affinity in other hemoglobin molecules. This results in tissue hypoxia, which induces Epo production. The rise in hematocrit is compounded by the reduction in plasma volume due to smoking.
• Defects in bisphosphoglycerate mutase and phosphofructokinase result in decreased 2,3 BPG. BPG is necessary for hemoglobin to transition from a high oxygen affinity state to a low oxygen affinity state. Thus a decreased BPG level results in tissue hypoxia in erythrocyte enzyme defect polycythemia
• Individuals with hemoglobinopathy with high affinity mutations (autosomal dominant inheritance) are unable to transition from high oxygen affinity to low oxygen affinity states due to impaired intramolecular rotation or BPG binding. Deoxygenation is impaired in some cases.
• Methemoglobinemia is usually due to a cytochrome b5 reductase (methemoglobin reductase) deficiency but can also be caused by various mutations of globin genes, such as Hemoglobin M. 
• Cobalt is believed to inhibit oxidative metabolism controlling Epo production. It is not effective treatment for anemia. Cobalt has been used as a foam stabilizer in beer and has been shown to cause an acquired polycythemia when unintentionally ingested in high amounts.
• Physiologically inappropriate polycythemia is often due to exogenous sources of erythropoietin.
• Several malignancies have been shown to produce erythropoietin. These include hepatoma, renal cell carcinoma and cerebellar hemangiomas. Uterine myomas have been reported to produce erythropoietin. However, another mechanism by which these often large bulky tumors produce erythrocytosis is mechanical interference with the blood supply to the kidneys resulting in false sensing of hypoxia and Epo production.
• Endocrine disorders such as pheochromocytomas, aldosterone producing adenomas, Barter syndrome, and dermoid cysts of the ovary can result in inappropriate Epo through mechanical interference with renal blood supply or hypertensive damage to renal parenchyma resulting in false sensing of hypoxia by the kidneys and subsequent Epo production, functional interaction between aldosterone, renin and erythropoietin, and inappropriate Epo secretion by the tumor. Androgens increase hematocrit by 2 mechanisms: stimulation of Epo production and an independent hyperproliferative effect on erythrocyte precursors.
• Chuvash polycythemia is an endemic polycythemia found on the west bank of the Volga River in the Chuvash Autonomous Republic in western Russia. It is an autosomal recessive disorder characterized by a mutation in the VHL gene that prevents ubiquitin degradation of hypoxia inducible factor (HIF)-1, resulting in upregulation of downstream target genes, including Epo production. As such, Chuvash polycythemia can be grouped with the secondary inappropriate polycythemias. But because of a second defect resulting in hyper-responsiveness to erythropoietin, not linked to the EpoR, it also has some features of primary polycythemia. Clinically, patients with Chuvash polycythemia have normal ABG, normal calculated p50 of hemoglobin, normal to increased Epo levels, and no abnormal hemoglobins.
• Rare mutations of HIF2a or proline dehydrogenase type 2 genes are associated with secondary congenital polycythemia; because of their rarity, the phenotype is not fully elucidated as yet.
• Renal polycythemia is due to Epo produced by renal cysts, polycystic disease, or hydronephrosis.
• Erythrocytosis can occur after renal transplant and is thought to be due to increased activity of the angiotensin II-angiotensin receptor 1 pathway. Angiotensin II may also modulate release of Epo and insulinlike growth factor (IGF)-1. Venous canalization studies have shown the source to be the "nonfunctional" native kidneys. Removal of the native kidneys can normalize the hematocrit; however ACE inhibitors can also control this typically transient erythrocytosis, thus avoiding surgery.
• Neonatal polycythemia is an appropriate secondary polycythemia due to increased oxygen affinity of fetal hemoglobin and subsequent tissue hypoxia. This response can become excessive and inappropriate in the setting of maternal diabetes or placenta to child transfusion.

Workup

Laboratory Studies

Once polycythemia vera (PV) is suspected, the first step in evaluating a patient is determining whether the patient has primary, secondary, or apparent polycythemia.

• A CBC count, ABG measurement, venous blood gas (VBG), and erythropoietin level can be used to differentiate patients. A CBC typically reveals increased leukocytes, platelets, and erythrocytes in primary polycythemia, whereas, in secondary and apparent polycythemia, only the erythrocytes are elevated. Primary familial congenital polycythemia (PFCP) is an exception; it only has elevated erythrocytes but not leukocytes or platelets. However, it can be distinguished from secondary polycythemia by its erythropoietin level. An erythropoietin (Epo) level is almost always low or low-normal in primary polycythemia; in secondary polycythemia, it is elevated or high-normal when hematocrit is high. Budd-Chiari syndrome in patients with the JAK2V617F mutation and elevated Epo levels has changed this absolute criteria in the diagnosis of polycythemia vera. An ABG reveals secondary appropriate polycythemia if it revealshypoxia. Finally,the VBG allows calculation of the P50 value; if this is low, it suggestsa high oxygen affinity hemoglobin or 2,3-bisphosphoglycerate (BPG) deficiency.
• Ferritin levels may also help differentiate between primary and secondary polycythemias. Typically in primary polycythemia, the ferritin level is low due to constant overproduction of erythrocytes. In contrast, the ferritin level is usually normal in secondary polycythemia.
• Red cell mass has been used to distinguish apparent polycythemia from secondary and primary polycythemia. However, the test is expensive and requires expertise. Also, the¹³¹ I-albumin used to measure plasma volume is not available in the United States and is difficult to handle because of its radioactivity. Consequently, the authors do not routinely use this test at the University of Utah School of Medicine because its diagnostic value is limited when the hematocrit level is clearly abnormal. The use of this test is frequently limited in clinical practice due to availability; however, some clinicians feel very strongly about it, especially in patients with borderline hemoglobin levels. It can occasionally identify a patient with an elevated red cell mass whose hematocrit is normal because of an increased plasma volume and can also identify patients whose hematocrit is only elevated due to a reduced plasma volume.
• Secondary polycythemia must be differentiated into appropriate and inappropriate causes. As mentioned above, an elevated Epo level with a hypoxic ABG suggests secondary appropriate polycythemia, whereas an elevated Epo level without hypoxia suggests secondary inappropriate polycythemia. Determining the cause of appropriate polycythemia can proceed using the history, although specialized testing such as a p50 curve can be used to identify high-affinity hemoglobins due to structural hemoglobin defects or enzyme deficiencies. Hemoglobin electrophoresis is insufficient to identify hemoglobin structural defects because some hemoglobin mutants are missed. Secondary inappropriate polycythemia causes can be sorted out using judicious imaging and specialized endocrine testing.
• Of the primary polycythemias, PFCP must be differentiated from polycythemia vera. These 2 diagnoses differ in clonality and in vitro responsiveness of peripheral blood erythroid progenitors to erythropoietin. Clonality testing relies on polymorphisms based on X chromosome inactivation and therefore can only be done in females. Polycythemia vera is clonal; PFCP is not. Endogenous erythroid colony responsiveness to Epo also differentiates polycythemia vera from PFCP. Polycythemia vera is characterized by growth independence from erythropoietin. In contrast, PFCP is not growth independent from erythropoietin, although it is hyperresponsive. Endogenous erythroid colony testing is not routinely available and can only be done in specialized laboratories. The authors frequently use it in our laboratory in difficult cases.

Imaging Studies

• CT scan or ultrasonography of the abdomen can be used to assess the size of the spleen which is frequently enlarged in polycythemia vera. 
• Renal pathology, cerebellar hemangioblastomas, and pheochromocytomas that can cause secondary polycythemia may also be detected.

Histologic Findings

• Bone marrow and aspirate in polycythemia vera tend to be hypercellular. 
• Some evidence of myelofibrosis may also be present.
• In the plethoric phase, the blood smear shows normal erythrocytes, variable neutrophilia with myelocytes, metamyelocytes, and varying degrees of immaturity, basophilia, and increased platelets.
• In the spent phase, the blood smear shows abundant teardrop cells, leukocytosis (or leukopenia), and thrombocytosis (or thrombocytopenia).

Staging

Because many practitioners do not have access to specialized clonality testing or erythroid colony assays, many of the criteria for diagnosis of polycythemia vera do not require them, although they are taken into account. No consensus has been reached on diagnostic criteria.

• The World Health Organization (WHO) criteria for polycythemia vera diagnosis requires 2 components: reasonable elimination of apparent and secondary polycythemia and confirmation of polycythemia vera. However, the discovery of the JAK2V617F mutation have made these criteria insufficient. A proposed set of revised criteria have recently been published.
• Proposed revised WHO criteria for polycythemia vera: Diagnosis requires the presence of both major criteria and one minor criterion or the presence of the first major criterion together with 2 minor criteria.^11,12
  • Major criteria
    • Hemoglobin level of more than 18.5 g/dL in men, more than 16.5 g/dL in women, or other evidence of increased red cell volume (hemoglobin or hematocrit levels >99^th percentile of method-specific reference range for age, sex, altitude of residence; hemoglobin level >17 g/dL in men, >15 g/dL in women [if associated with a documented and sustained increase of at least 2 g/dL from the individual’s baseline value that cannot be attributed to correction of iron deficiency], or elevated red cell mass >25% above mean normal value).
    • Presence of JAK2V617F or other functionally similar mutation such as JAK2 exon 12 mutation
  • Minor criteria
    • Bone marrow biopsy showing hypercellularity for age, with trilineage growth (panmyelosis) with prominent erythroid, granulocytic, and megakaryocytic proliferation (not validated in prospective studies)
    • Serum erythropoietin level below the reference range for normal
    • Endogenous erythroid colony formation in vitro
• Other groups have proposed and are preparing other potential diagnostic criteria. Criticism of the new WHO 2008 revised criteria revolves around the substantial interobserver variability in diagnosing polycythemia vera by bone marrow histology and the difficulty of community practitioners to test for endogenous erythroid colonies.

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